Google Health, the new service offered by Google is now online (via bbgm, Life as a Healthcare CIO, GTO). This service helps users to store, organize and share their health profile and medical records, to use a variety of health-related online services and to search for medical information. Understandably, Google places great emphasis on data security and confidentiality. In this regard, I thought it might be worth highlighting several recent and thought-provoking discussions around the issues of data privacy and participative medical investigations.

In a provocative editorial (Bains, 2007, see also Nature Medicine News article), William Bains advocates that collectives of individuals, so-called 'Biomedical Mutual Organization', could organize themselves on a voluntary and self-funded basis to conduct clinical trials that would rely on extensive self-experimentation, data sharing and pooling of analytical resources. This proposal challenges the classical view that those who conduct a clinical trial should avoid conflicts of interest with respect to the outcome of the trial. On the other hand, Bains argues, this system would allow more innovative and radical trials to be performed, given that the subjects of the trial would have increased trust in the research process (being their own trial managers) and, hopefully, a more accurate perception of the risk/benefit balance involved.

Another radical proposal is the concept of 'open-consent' as currently applied within George Church's Personal Genome Project (Church, 2005). Jeantine Lunshof, George Church and colleagues highlight in a recent review (Lunshof et al, 2008) the limitations of the current definitions of genetic privacy and confidentiality in view of the rapid advances in the fields of human genetics and personal genomics. In particular, the creation of large database interlinking individual genome-wide genotypes to extensive phenotypic profiles will make de-identification of such datasets increasingly difficult if not impossible (Lowrance and Collins, 2007). Under these conditions, it appears that the promise of absolute anonymity and confidentiality of private data is becoming unrealistic. Church and colleagues affirm that an 'open-consent' policy would avoid making such false promises and would therefore represent a more realistic way to formulate an adequately informed consent when accepting to participate to a human genomic research study.

At last month's ESF Conference on Systems Biology, Hiroaki Kitano discussed the potential of multi-component, combinatorial therapies (see also Kitano, 2007). He introduced the tentative idea of an 'Open Pharma' strategy, which would attempt to exploit beneficial synergistic effects that may result from combined administration of cheap generic drugs. He envisions that this type of approach could ultimately lead the way to novel and hopefully more affordable therapeutic strategies, which would provide a potential alternative to the current single-target proprietary drug paradigm.

Observing the launch of Google Health within the context of this series of rather revolutionary proposals, it is tempting to imagine for a moment what would result from large-scale self-experimentation with multi-component generic drug cocktails combined with web-enabled data sharing under some form of open-consent... Will 'Participative Open Pharma' be our future?

Two rather contrasting videos on synthetic biology this month. In the first videocast, released by TED, Craig Venter exposes his grand vision of synthetic genomics. He insists on the notion of 'combinatorial genomics', that will combine the power of large scale DNA synthesis ('robots that can make a million chromosomes a day') with a database of 20 million genes, 'the design components of the future'. This approach, a pragmatic mixture of rational function-oriented design and empirical large-scale selection, is envisioned to prepare a modern 'Cambrian explosion' of new synthetic species. It is good to see Craig Venter laughing when announcing casually the 'modest goal of replacing the entire petro-chemical industry'. In any case, Craig Venter appears to be more concerned that the technology may not develop sufficiently rapidly to match the urgency and scale of the major ecological and medical challenges faced by our planet than by potential threats represented by harmful biohacking and bioterror.

The second video, admittedly less entertaining, is a recording of the recent deliberations of the National Science Advisory Board for Biosecurity (NSABB). In his presentation entitled 'Assessing Biosecurity Concerns Related to Synthetic Biology', David Relman presents some preliminary findings and recommendations of the Working Group on Synthetic Genomics (jump to 1hr:34min:37sec). It is interesting to see that no consensus definition of synthetic biology exists among the various practitioners of the field, who all use different blends of the typical bottom-up engineering approach assembling circuits from standard components and top-down strategy, based on the modifications of existing genomes. Beyond the lack of definition, the current ability to predict biological functions from sequence (eg virulence) remains very limited complicating the possibility of realistic risk assessment. Finally, the development of synthetic biology can be seen as an extension of the success of 'kit-based' molecular biology, which facilitates access of these technologies to groups outside the traditional Life Sciences communities and institutions, making the mission of oversight, outreach and eduction more challenging. David Relman also clearly emphasizes the importance of not discouraging the enthusiasm directed towards potentially beneficial research and applications by overzealous oversight and regulations.

The intersection between the two talks above was perhaps made when the question of virulence was raised (jump to 1hr:59min:35sec). The fraction of pathogenic agents is very small compared to the number of existing species, a point also made by Craig Venter, and the rate of appearance of new pathogens is low. The idea was then raised as whether it would be possible to roughly estimate the risk of creating synthetic pathogens by calculating the likelihood that the amount of natural recombination responsible for the emergence of new pathogens 'in the wild' could be matched by an equivalent amount of experimental recombination in the laboratory. In other words, is there any way to estimate the probability that new forms of virulence could emerge from the announced synthetic 'Cambrian explosion'?

(via Scintilla)

The article on "Probiotics modulation of mammalian metabolism" published this week in Molecular Systems Biology by Jeremy Nicholson and colleagues (Martin at al, 2008) has attracted some attention (read the nice summary in Science News) in some (very) popular media (here, here, here and here).

In this follow-up study of the paper published last year (Martin et al, 2007), the team lead by Jeremy Nicholson, in collaboration with Nestlé, demonstrates clear physiological effects of oral probiotics administration on mice harbouring a humanized microbiome. The effects are intricate: both the host flora and metabolism are altered. By analyzing metabolite pools in several compartments (liver, blood, urine, feces, gut), and following in parallel the host microbiota, patterns of correlations between microbial species and metabolites start to be visible and reveal the probiotics-induced modulation of the microbial-mammalian interactions. But the actual paper is really just next door (synopsis), so have a look...

How will these results translate to humans? What will be the best way to influence our microbiome? Drugs or yoghurt? These are fascinating questions and the understanding of how our physiology depends on the microbial flora could have profound consequences, particularly in these times when we seem to be in a "rush to gene-based solutions to all our problems" (Wilson, 2007). Will personal genomics have to ultimately develop into personal metagenomics to include our "extended" microbial genome?

Even if I usually prefer to resist the temptation of a self-promoting section in this blog, I find the attention of the media for this topic interesting (despite the usual variable accuracy of newspaper reports) because it points to an area where systems biology provides insights into topics of immediate interest to the general public.

The NIH has recently started its Human Microbiome Project. In this context, this study also underscores the importance of developing model systems and tools to manipulate the microbiome and to analyze the incredibly dense and intricate interactions that connect host and microbial species. A field where top-down systems biology seems indeed a very pragmatic and promising approach.

I highly recommend to visit the NIH VideoCasting page, which hosts many interesting video/podcasts. Even if I realize that this is a bit old according to the blogosphere time scale, I would like to point to this one: "The Future: Consumer Health Information Technology", featuring talks given at a NCI-sponsored meeting on Dec 10, 2007 by Adam Bosworth (formerly "Google Health architect", now starting his own company Keas), Bern Shen (Intel) and Bill Crounse (Microsoft).

In his introduction to the meeting, Bradford Hesse (NCI) colorfully summarizes one of the main concepts exposed by the speakers (the video is very long, so I give some pointers: 0h16min43sec) by comparing the future of healthcare to...an "IKEA flat pack": patients will progressively be empowered to assemble their own care from home, like they would build a piece of (cheap) furniture.

Adam Bosworth (0h25min53sec) presents his very pragmatic vision of how IT could concretely help healthcare (0h39min07sec): a) help the consumer to own and control his personal health data, and this already for very simple basic information; b) provide tools for doctors so that they can deliver personalized care as easily as producing a spreadsheet; c) develop tools for researchers to facilitate the design and implementation of new protocols and clinical trials.

Bill Crounse (Microsoft's other Bill...1h14min30sec) sees 5 major current trends that will increasingly challenge the healthcare system and call for IT solutions (1h26min22sec): a) increasing personal responsibility ("the end of health insurance"); b) progressive "retailization" of healthcare services (eg appearance of "retail minute clinics"); c) commoditization of healthcare providers; d) globalization of access to information (through the web of course); e) globalization of healthcare services. I recommend his little funny anecdote on the high-tech GPS wireless-connected plumber (1h25min30sec) who appears to better equipped than any practicing physician...

The speakers also all insist on the need for massive data integration promoted by the interoperability of formats and coding information, themes that probably sound familiar to many systems biologists.

Toward the end of his talk (1h35min00sec), Bill Crounse shows a short "science-fiction" movie on Microsoft's vision of the future of healthcare: a world full of credit-card sized tablet PCs, touch screens and many other very exciting gadgets (I love gadgets!). But I can't help missing a bit the warmth of human-to-human interactions within this jungle of virtual consultations, retail clinics, remote controlled metabolic parameters, etc... and I didn't quite see in that movie that the doctor would spend more time with his patient or the daughter with her sick Grandma. But this may of course only reflect some old-fashioned side of my temperament...

The wave of personal genomics is progressing rapidly. A string of four papers appeared recently (Porreca et al, 2007, Albert et al, 2007, Okou et al 2007, Hodges et al, 2007) reporting on microarrray-based technologies that enable the enrichment of selected genomic fragments in a single massively multiplexed reaction, thus greatly facilitating subsequent resequencing of pre-defined portions of the human genome (eg all coding exons). These technologies are expected to reduce dramatically the cost of targeted resequencing of individual genomes.

On the commercial front, deCODE and 23andMe have launched their personal genome service offering genome-wide SNPs profiling for a little less than $1,000 (NYT articles: Nicholas Wade, Amy Harmon, or Wired, ScienceRoll, Sandra, DNA and You).

The chips used by 23andMe are the "Illumina HumanHap550+ BeadChip, which reads more than 550,000 SNPs (single nucleotide polymorphisms) plus a 23andMe custom-designed set that analyzes more than 30,000 additional SNPs." The profile provided by deCODEme includes "over one million variants across the genome."

So what do you think?

The Royal Society seeks your views on the emerging area of synthetic biology. This is your opportunity to shape the focus of the Royal Society's policy future work in this important area. We welcome views from individuals or organisations by 27 August 2007.

• Potential developments and applications
• Current research capacity and geographical distribution
• Societal implications
• Ethical concerns
• Biosecurity risks
• Implications for the environment
• Research support and funding
• Implications for human health
• Legal issues and implications for regulation (national and international)
• Ownership, sharing and innovation frameworks (including intellectual property)
• Biosafety concerns
• Education and training
• Governance and oversight of research
• Economic considerations for developed and developing countries

Last April, the US National Science Advisory Board for Biosecurity issued a draft report on Biosecurity (see post below). One point of criticism expressed with regard to this report was that it did not address explicitly concerns specific to synthetic biology.

In a Commentary published in Nature Biotechnology (Bügl et al, 2007), a panel of scientists, executives from the DNA-synthesis industry and members of the US FBI present now their views and concrete recommendations on measures required for an efficient and practical oversight of DNA-synthesis activities.

Rapid progresses in DNA-synthesis technologies are increasingly challenging the current safety measures and oversight mechanisms that were tailored for recombinant DNA technologies (Berg et al, 1975). Two major sources of concerns are expressed by the authors with regard to the combination of facile DNA-synthesis, very short delivery time and internet-based communication: 1) the processes of design, assembly and use of engineered genetic material can be "decoupled" and performed in a fragmented way across different locations, rendering tractability of the overall process difficult; 2) DNA-synthesis may provide a workaround strategy to circumvent the existing physical barriers and containment strategies that currently regulate access to pathogens.

The goals of the proposed oversight framework are listed as follows in Bügl et al:

First, the framework should promote and later compel responsible behavior on the part of users of DNA-synthesis technology. Second, the framework should be sufficiently simple and robust be adopted as best practice throughout industry. Third, the framework should enable common improvement of needed technologies and promote sharing of operational wisdom throughout industry and government. Fourth, the framework should build on the existing practices that have enabled the safe development and application of recombinant DNA technology over the past three decades. Finally, the framework should foster and support international transparency and cooperation.

To achieve these objectives, the authors suggest an initial scheme on how users, industry and government may interact to implement the proposed framework. At the individual level, customers should identify themselves, provide relevant biosafety information and observe local accountability mechanisms. At the corporate level, companies would implement state-of-the-art screening methods and directly cooperate with governments to identify suspicious DNA orders.

In addition, a group of DNA-synthesis companies have formed an "International Consortium for Polynucleotide Synthesis" (ICPS), of which some authors are member, and is proposed to serve as an interface between government agencies and synthetic biology companies.

see also: NSABB Report "Addressing Biosecurity Concerns Related to the Synthesis of Select Agents" (pdf download)

In a News&Views just published in Molecular Systems Biology, Joachim Henkel & Stephen Maurer expose their views on the economics of synthetic biology (Henkel and Maurer, 2007):

Synthetic biology contains almost all of the same ingredients that make embedded Linux successful. First, synthetic biology's parts approach emphasizes strong modularity. This allows the work of creating a parts library to be spread over many companies. It also makes it possible for companies to earn profits by patenting some parts while making others openly available. Second, we expect companies to have fairly idiosyncratic parts needs. This means that they cannot simply 'free ride' by waiting for others to make what they need. It also suggests that companies can often share parts without losing their technological 'edge' to competitors. Third, different companies will have different expertise. This suggests that community-based libraries will often outperform company ones. Finally, the synthetic biology market will probably include large numbers of small, idiosyncratic customers. This makes patent licensing less lucrative and, by comparison, openness more attractive.

Synthetic biology is defined around the concept of standardized re-usable parts. A piece of C++ code is very very very well behaved and therefore highly suitable for a development model based on sharing parts. In synthetic biology, as Ron Weiss writes (Andrianantoandro et al, 2006),

the engineering strategies of standardization, decoupling, and abstraction can also be useful tools for dealing with the complexity of living systems...The above engineering strategies come from disciplines where components are well behaved, easy to isolate from each other, and can subsist in isolation. The strategies must be adapted to work well in the biological realm, where biological components cannot exist without being connected....Design and fabrication methods that take into account uncertainty and context dependence will likely lead to on-demand, just-in-time customization of biological devices and components, which need not behave perfectly. Building imperfect systems is acceptable, as long as they perform tasks adequately."

How close will synthetic biology come to something like object-oriented programming? The future will tell how far the analogy with the "embedded Linux" model can be extended and whether the economics of synthetic biology will be influenced by how "well behaved" and complex synthetic parts are.

Observations suggest that current climatic models may underestimate how quickly the climate system is changing (in particular for sea level), according to a report in Science a few weeks ago (Rahmstorf et al, 2007). Another Science paper published last week shows that the capacity of the Southern Ocean CO₂ sink is weakening, which may result in increased atmospheric CO₂ levels in the long run (Le Quere et al, 2007).

I remember Hiroaki Kitano calling the systems biology community, in his talk at the ICSB meeting last October in Yokohama, for ideas on how system-level approaches could contribute to address the challenge of global warming. In response to the studies above, a similar call is now sent to the microbiology community by Jonathan Eisen on his blog. Research topics suggested in his post include:

Marine Microbiology

Carbon fixation processes

Hydrogen production

Carbon sequestration

Methane capture

Microbial fuel cells

A similar list of priorities related to energy challenges, environmental remediation and carbon cycling and sequestration can be found on the site of the Genomics:GTL research program from the US Department of Energy.

For all the topics listed above, systems biology and synthetic biology approaches are likely to be crucial not only to accumulate the necessary fundamental knowledge but also to find ways to translate it into technological applications. Proposals, insights and visionary suggestions are more than welcome...

some additional links:
Special issue on Energy and Sustainability
ASM Report on Microbial Energy Conversion
Microbial ecology meets electrochemistry: electricity-driven and driving communities. Rabaey et al, 2007, The ISME Journal 1:9

Novartis, The Broad Institute, and Lund University today announced the completion of a genome-wide map of genetic differences in humans and their relationship to type 2 diabetes and other metabolic disorders. All results of the analysis are being made accessible, free of charge on the internet to scientists around the world (Novartis Media Release, Feb 12, 2007)

The results of this study are available at http://www.broad.mit.edu/diabetes/

Has the increasing complexity of genome-wide studies and other large-scale systems biology datasets reached a threshold that makes the open source option more attractive to the pharma industry?